Neutrophils, which is a type of granulocytes, have migratory, phagocytic, and microbicidal activities, and play important roles in biological protection against infectious agents such as bacteria or fungi. There are some diseases associated with neutrophils.
Neutrophilic functional disorders, in which one or more of the above-mentioned biological activities of neutrophils are impaired, include, for example, lazy-leukocyte (chemotaxis-deficient leukocyte) syndrome, one of the neurotaxis deficient diseases. In patients affected with this syndrome, neutrophils are markedly decreased in number in the peripheral blood, and their migratory activity is impaired, although they are present at a normal level in the bone marrow. Patients suffering from neutrophilic functional disorders are very few, and drugs applicable to the disorders are so far not commercially available.
Another example of the diseases associated with neutrophils is inflammatory diseases. Inflammatory reaction is a biological protection to tissue damages caused by inflammatory stimulation (e.g., foreign bodies such as bacteria or others, and physicochemical stimulation, etc.). The inflammatory reaction basically removes harmful stimulation from the living body and restores local tissue structures and functions. The activated inflammatory system is, however, toxic to normal tissues and cells, and the strongly expressed inflammatory reaction should be suppressed.
The inflammatory reaction includes three major processes; 1) increment of blood supply to infected sites; 2) enhancement of vascular permeability due to the reaction in vascular endothelial cells; and 3) mobilization of leukocytes, specifically, neutrophils and some macrophages, from capillaries to tissues, and subsequent migration to infected sites. These processes result in accumulation and infiltration of neutrophils as well as macrophages at their target sites. Thus repressing the neutrophilic functions has been believed to be effective for controlling the inflammatory reaction.
Various anti-inflammatory drugs have been developed. They are categorized into two groups, non-specific anti-inflammatory drugs (steroidal anti-inflammatory drugs and non-steroidal anti-inflammatory drugs) and specific anti-inflammatory drugs (anti-rheumatic drugs, anti-podagric drugs, immunosuppressants, etc.). Analgesic and anti-inflammatory drugs (non-steroidal anti-inflammatory drugs, NSAIDs) are used mainly, and anti-rheumatic drugs (disease-modifying anti-rheumatic drugs, DMARDs) and steroidal drugs are used secondarily, in chemotherapy for rheumatoid arthritis (RA). However, NSAIDs cause acute gastric mucosal lesions (AGML), and are thus often used in the form of prodrugs to avoid AGML.
Recently, midkine (MK) has been identified as a heparin-binding polypeptide with the molecular weight of 13 kDa and a retinoic acid-inducible gene product. Reported midkine functions include maintaining and differentiating embryonic nerve cells and enhancing neurite extension; promoting division of specific cell lines (Muramatsu, H. et al., Biochem. Biophys. Res. Commun. 177: 652-658, 1991; and Michikawa, M. et al., J. Neurosci. Res. 35: 530-539, 1993; Muramatsu, H. et al., Dev. Biol. 159: 392-402, 1993); regulating embryonic development (Kadomatsu, K. et al., J. Cell. Biol. 110: 607-616, 1990; Mitsiadis, T. A. et al., Development 121: 37-51, 1995); etc. Furthermore, anti-midkine antibody reportedly inhibits dentition in vitro (Mitsiadis, T. A. et al, J. Cell. Biol. 129: 267-281, 1995).
It has been revealed that midkine plays crucial roles in restoration of damaged tissues and some diseases. The expression patterns of midkine were investigated in various human carcinomas. The studies revealed that midkine expression is elevated in various cancers including stomach cancer, colon cancer, pancreatic cancer, lung cancer, thoracic cancer, and liver cancer (Tsutsui, J. et al., Cancer Res. 53: 1281-1285, 1993; Aridome, K. et al., Jap. J. Cancer Res. 86: 655-661, 1995; and Garver, R. I. et al., Cancer 74: 1584-1590, 1994). The high-level expression of midkine correlates with unfavorable prognoses in patients affected with neuroblastoma (Nakagawara, A. et al., Cancer Res. 55: 1792-1797, 1995). Midkine accumulates in senile plaques of most patients with Altzheimer's disease (Yasuhara, O. et al. Biochem. Biophys. Res. Commun. 192: 246-251, 1993). Midkine is expressed in regions with edema at early stages of cerebral infarction (Yoshida, Y. et al., Dev. Brain Res. 85: 25-30, 1995). These findings indicate that midkine may be associated with restoration of damaged tissues and tissue abnormalities that are signs of some diseases.